Malaria is a devastating infectious disease caused by the protozoa Plasmodium falciparum. Malaria affects about 200-500 million people worldwide annually, killing almost 1% of those infected (Madrid et al., Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities, Bioorg. Med. Chem. Lett., 2005, 15, 1015-8). Four species of Plasmodium infect humans, the most deadly of these being P. falciparum. Most deaths occur due to a complication of infections with P. falciparum, wherein erythrocytes infected with mature-stage parasites adhere to the vascular endothelium of post-capillary venules. Vascular occlusion and/or an inappropriate host immune reaction can lead to coma. Once a coma is established, the subject usually has only a 10-50% chance of survival, even with appropriate medical attention.
Malarial drug resistance is largely responsible for the current epidemic and thus the discovery of new effective antimalarial agents is needed. Quinoline-based therapies are commonly used for the treatment of malaria. However, because of their widespread use, many malaria parasites are now resistant to traditional quinoline-based therapies. Drug resistance to the commonly used malaria drug, Chloroquine (CQ), for example, is so widespread that the drug is virtually useless in some parts of the world. Although numerous small molecules demonstrating superior antimalarial properties are regularly being discovered, most of these compounds fail to reach the clinic in part due to their poor pharmacokinetic and toxicity profiles. Thus, it is imperative that new anti-malarial strategies be developed, and in particular, new therapies that are effective against drug-resistant malaria. The present application addresses this need.